Background Understanding the regulatory role of enhancer–promoter interactions (EPIs) on specific gene expression in cells contributes to the understanding of gene regulation, cell differentiation, etc., and its identification has been a challenging task. On the one hand, using traditional wet experimental methods to identify EPIs often means a lot of human labor and time costs. On the other hand, although the currently proposed computational methods have good recognition effects, they generally require a long training time. Results In this study, we studied the EPIs of six human cell lines and designed a cell line-specific EPIs prediction method based on a stacking ensemble learning strategy, which has better prediction performance and faster training speed, called StackEPI. Specifically, by combining different encoding schemes and machine learning methods, our prediction method can extract the cell line-specific effective information of enhancer and promoter gene sequences comprehensively and in many directions, and make accurate recognition of cell line-specific EPIs. Ultimately, the source code to implement StackEPI and experimental data involved in the experiment are available at https://github.com/20032303092/StackEPI.git. Conclusions The comparison results show that our model can deliver better performance on the problem of identifying cell line-specific EPIs and outperform other state-of-the-art models. In addition, our model also has a more efficient computation speed.